HHS Public Access Author manuscript Author Manuscript
Dev Psychobiol. Author manuscript; available in PMC 2017 January 18. Published in final edited form as: Dev Psychobiol. 2015 November ; 57(7): 833–841. doi:10.1002/dev.21332.
Catechol-O-methyltransferase Val158met Polymorphism Interacts With Early Experience to Predict Executive Functions in Early Childhood Clancy Blair1, Michael Sulik1, Michael Willoughby2, Roger Mills-Koonce2, Stephen Petrill3, Christopher Bartlett4, Mark Greenberg5, and The Family Life Project Investigators6
Author Manuscript
1Department
of Applied Psychology NYU, 246 Greene St, Kimball Hall, 8th floor New York, NY
10003 2Frank
Porter Graham Child Development Center 521 S. Greensboro Street, CB 8185 NC 27599
3Department
of Psychology The Ohio State University, 1835 Neil Avenue Columbus, OH 43210
4The
Research Institute at Nationwide Children's Hospital & The Ohio State University 575 Children's Crossroad WB5149 Columbus, OH 43215
5Department
of HDFS, 110 Henderson South Pennsylvania State University, University Park PA
16802 6Center
for Developmental Science 100 E. Franklin St., CB8115, UNC Chapel Hill Chapel Hill, NC
27599
Author Manuscript
Abstract
Author Manuscript
Numerous studies demonstrate that the Methionine variant of the catechol-O-methyltransferase Val158Met polymorphism, which confers less efficient catabolism of catecholamines, is associated with increased focal activation of prefrontal cortex (PFC) and higher levels of executive function abilities. By and large, however, studies of COMT Val158Met have been conducted with adult samples and do not account for the context in which development is occurring. Effects of early adversity on stress response physiology and the inverted U shape relating catecholamine levels to neural activity in PFC indicate the need to take into account early experience when considering relations between genes such as COMT and executive cognitive ability. Consistent with this neurobiology, we find in a prospective longitudinal sample of children and families (N=1292) that COMT Val158Met interacts with early experience to predict executive function abilities in early childhood. Specifically, the Valine variant of the COMT Val158Met polymorphism, which confers more rather than less efficient catabolism of catecholamines is associated with higher executive function abilities at child ages 48 and 60 months and with faster growth of executive function for children experiencing early adversity, as indexed by cumulative risk factors in the home at child ages 7, 15, 24, and 36 months. Findings indicate the importance of the early environment for the relation between catecholamine genes and developmental outcomes and demonstrate that the genetic moderation of environmental risk is detectable in early childhood.
Correspondence to: Clancy Blair [email protected].
Blair et al.
Page 2
Author Manuscript
Keywords
early experience; polymorphism; stress; attention
INTRODUCTION
Author Manuscript
The relation of catecholamines to cognitive functions associated with prefrontal cortex (PFC) is well established. Numerous studies have demonstrated that the functional form of this relation is that of an inverted U shape curve (Arnsten, 2009). Moderate increases in dopamine and norepinephrine are associated with increased synaptic activity and higher levels of performance on executive function tasks as assessed by measures of working memory and the ability to shift cognitive set. In contrast, very high or very low levels are associated with reduced synaptic activity in PFC and poor executive cognitive performance. This inverted U shape relation between catecholamine levels and performance on tasks dependent on PFC represents a neurobiological manifestation of the now over 100-year-old Yerkes-Dodson law (Diamond, Campbell, Park, Halonen, & Zoladz, 2007).
Author Manuscript
Given the association between catecholamine levels and cognitive functions associated with PFC, research on the genetic basis for executive functions, particularly working memory, has focused on variants of candidate genes associated with catecholamine activity in the brain. For example, numerous studies have examined variants of the catechol-O-methyltransferase (COMT) gene as well as variants of dopamine receptor and monoamine oxidase genes. COMT is a complex gene with multiple relevant polymorphisms (Nackley et al., 2006); however, the Val158Met polymorphism has been widely studied in adult populations but infrequently examined in children. This variant, a valine to methionine substitution at codon 158, results in less efficient catabolism of catecholamines, particularly, dopamine, leading to the hypothesis that individuals with this substitution will exhibit higher levels of executive function ability in studies conducted in controlled laboratory settings (Tunbridge, Harrison, & Weinberger, 2006).
Author Manuscript
By and large, examinations of catecholamine genes, including COMT, have tended to demonstrate hypothesized relations between gene variants and neural activity. The findings of this literature generally support the idea that higher catecholamine availability (less efficient catabolism) is associated with more efficient activation of PFC in response to executive function tasks (Mier, Kirsch, & Meyer-Lindberg, 2010). Findings for the relation of the COMT Val158Met polymorphism to measured executive function ability, however, are mixed (Barnett, Heron, Goldman, Jones, & Xu, 2009; Barnett, Scoriels, & Munafò, 2008; Goldman, Weinberger, Malhotra, & Goldberg, 2009). Given the inverted U shaped association between catecholamine levels and executive cognition, the empirical literature is particularly clear on the need to take into account resting or pretask catecholamine levels when examining the relation of COMT genotype to measured executive cognitive ability (Dickinson & Elvevåg, 2009). Specifically, studies demonstrate that increased catecholamine availability, as with the presence of the Met allele in Val158Met, is associated with greater executive cognitive ability when resting catecholamine levels are low, but with reduced executive cognitive ability when pretask levels are high (Mattay et al., 2003; Qin et
Dev Psychobiol. Author manuscript; available in PMC 2017 January 18.
Blair et al.
Page 3
Author Manuscript
al., 2012) or when COMT activity is inhibited (Farrell, Tunbridge, Brauetigam, & Harrison, 2012).
Author Manuscript
Although it is well established that background catecholamine levels are relevant to the relation of genes such as COMT to executive cognition, it is notable that few if any studies have examined the relation between COMT and executive cognitive ability using a prospective longitudinal design that takes into account the quality of early life experience. Adverse early experience, such as that associated with early life stress has been shown in both human and animal models to increase catecholamine and glucocorticoid output (Evans, 2003; McEwen and Gianaros, 2011; Meaney, 2001) and to be associated with a pattern of gene expression associated with increased reactivity and decreased regulation of the stress response (Miller et al., 2009). It is therefore likely that early life experience will moderate any relation between variation in the COMT gene and executive function ability. Specifically, among individuals with stressful early life experience, higher catecholamine availability due to less efficient catabolism, as in individuals with a Met allele for COMT Val158Met, would be associated with lower rather than higher executive function ability. In contrast, in keeping with the Yerkes-Dodson inverted U-shape curve, among individuals with greater early life stress, reduced catecholamine availability (more efficient catabolism) associated with the Val-Val genotype would be associated with higher executive function abilities.
Author Manuscript Author Manuscript
Given a theoretical and empirical basis for expected interaction between monoamine gene variants and early experience in the prediction of developmental outcomes, questions about the age in childhood at which associations among gene variants, early experience, and cognitive outcomes might be observed are of interest. Examination of COMT enzyme activity in postmortem human brain indicated a twofold increase between the neonatal period and adulthood (Tunbridge et al., 2006) with levels in childhood at approximately 50% of their adult values. Notably, one prior lab-based study with a small sample of children from middle to upper income homes found, as expected, an association between Met genotype and executive functions in 8 to 14 year olds (Diamond, Briand, Fossella, & Gehlbach, 2004). A second, with a large sequential cohort sample in Sweden found that the Val–Val genotype was associated with working memory ability in young children (age 6 years) but that the Met-Met genotype was associated with better working memory in early adolescence (Dumontheil et al., 2011). No prior studies of which we are aware, however, have examined interaction between COMT and early experience in children with sample sizes large enough to produce reliable estimates of interaction effects. It is not known whether variation in early adversity in the typical range might interact with genetic background to influence trajectories of aspects of development such as executive function abilities in childhood. Here, we examine expected gene-environment interaction with a diverse prospective longitudinal sample of children and families in predominantly non-urban and low-income communities in two regions of high poverty in the US. It has been shown previously in this sample that early environmental adversity was prospectively associated with elevated cortisol levels in children through age 48 months (Blair et al., 2011a), and that elevated cortisol in the early toddler period partially mediated a relation between early adversity and
Dev Psychobiol. Author manuscript; available in PMC 2017 January 18.
Blair et al.
Page 4
Author Manuscript
lower performance on a battery of executive function tasks (Blair et al., 2011b). Here, we build on these prior findings to test the hypothesis that COMT Val158Met genotype will interact with cumulative risk in the family environment in the prediction of executive function development between ages 3 and 5 years. Specifically, the valine variant of COMT Val158Met will be associated with a higher level of executive in the context of high early adversity while the methionine variant will be associated with a higher level of executive function in the context of low early adversity.
METHODS Participants
Author Manuscript
The Family Life Project (FLP) was designed to study young children and their families in two of the four major geographical areas of the United States with high poverty rates. Specifically, three counties in eastern North Carolina and three counties in central Pennsylvania were selected to be indicative of the Black South and Appalachia, respectively. The FLP adopted a developmental epidemiological design in which sampling procedures were employed to recruit a representative sample of 1,292 children whose families resided in one of the six counties at the time of the child's birth. Low-income families in both states and African American families in NC were over-sampled. African American families were not over-sampled in PA because African Americans made up
Dev Psychobiol. Author manuscript; available in PMC 2017 January 18. Published in final edited form as: Dev Psychobiol. 2015 November ; 57(7): 833–841. doi:10.1002/dev.21332.
Catechol-O-methyltransferase Val158met Polymorphism Interacts With Early Experience to Predict Executive Functions in Early Childhood Clancy Blair1, Michael Sulik1, Michael Willoughby2, Roger Mills-Koonce2, Stephen Petrill3, Christopher Bartlett4, Mark Greenberg5, and The Family Life Project Investigators6
Author Manuscript
1Department
of Applied Psychology NYU, 246 Greene St, Kimball Hall, 8th floor New York, NY
10003 2Frank
Porter Graham Child Development Center 521 S. Greensboro Street, CB 8185 NC 27599
3Department
of Psychology The Ohio State University, 1835 Neil Avenue Columbus, OH 43210
4The
Research Institute at Nationwide Children's Hospital & The Ohio State University 575 Children's Crossroad WB5149 Columbus, OH 43215
5Department
of HDFS, 110 Henderson South Pennsylvania State University, University Park PA
16802 6Center
for Developmental Science 100 E. Franklin St., CB8115, UNC Chapel Hill Chapel Hill, NC
27599
Author Manuscript
Abstract
Author Manuscript
Numerous studies demonstrate that the Methionine variant of the catechol-O-methyltransferase Val158Met polymorphism, which confers less efficient catabolism of catecholamines, is associated with increased focal activation of prefrontal cortex (PFC) and higher levels of executive function abilities. By and large, however, studies of COMT Val158Met have been conducted with adult samples and do not account for the context in which development is occurring. Effects of early adversity on stress response physiology and the inverted U shape relating catecholamine levels to neural activity in PFC indicate the need to take into account early experience when considering relations between genes such as COMT and executive cognitive ability. Consistent with this neurobiology, we find in a prospective longitudinal sample of children and families (N=1292) that COMT Val158Met interacts with early experience to predict executive function abilities in early childhood. Specifically, the Valine variant of the COMT Val158Met polymorphism, which confers more rather than less efficient catabolism of catecholamines is associated with higher executive function abilities at child ages 48 and 60 months and with faster growth of executive function for children experiencing early adversity, as indexed by cumulative risk factors in the home at child ages 7, 15, 24, and 36 months. Findings indicate the importance of the early environment for the relation between catecholamine genes and developmental outcomes and demonstrate that the genetic moderation of environmental risk is detectable in early childhood.
Correspondence to: Clancy Blair [email protected].
Blair et al.
Page 2
Author Manuscript
Keywords
early experience; polymorphism; stress; attention
INTRODUCTION
Author Manuscript
The relation of catecholamines to cognitive functions associated with prefrontal cortex (PFC) is well established. Numerous studies have demonstrated that the functional form of this relation is that of an inverted U shape curve (Arnsten, 2009). Moderate increases in dopamine and norepinephrine are associated with increased synaptic activity and higher levels of performance on executive function tasks as assessed by measures of working memory and the ability to shift cognitive set. In contrast, very high or very low levels are associated with reduced synaptic activity in PFC and poor executive cognitive performance. This inverted U shape relation between catecholamine levels and performance on tasks dependent on PFC represents a neurobiological manifestation of the now over 100-year-old Yerkes-Dodson law (Diamond, Campbell, Park, Halonen, & Zoladz, 2007).
Author Manuscript
Given the association between catecholamine levels and cognitive functions associated with PFC, research on the genetic basis for executive functions, particularly working memory, has focused on variants of candidate genes associated with catecholamine activity in the brain. For example, numerous studies have examined variants of the catechol-O-methyltransferase (COMT) gene as well as variants of dopamine receptor and monoamine oxidase genes. COMT is a complex gene with multiple relevant polymorphisms (Nackley et al., 2006); however, the Val158Met polymorphism has been widely studied in adult populations but infrequently examined in children. This variant, a valine to methionine substitution at codon 158, results in less efficient catabolism of catecholamines, particularly, dopamine, leading to the hypothesis that individuals with this substitution will exhibit higher levels of executive function ability in studies conducted in controlled laboratory settings (Tunbridge, Harrison, & Weinberger, 2006).
Author Manuscript
By and large, examinations of catecholamine genes, including COMT, have tended to demonstrate hypothesized relations between gene variants and neural activity. The findings of this literature generally support the idea that higher catecholamine availability (less efficient catabolism) is associated with more efficient activation of PFC in response to executive function tasks (Mier, Kirsch, & Meyer-Lindberg, 2010). Findings for the relation of the COMT Val158Met polymorphism to measured executive function ability, however, are mixed (Barnett, Heron, Goldman, Jones, & Xu, 2009; Barnett, Scoriels, & Munafò, 2008; Goldman, Weinberger, Malhotra, & Goldberg, 2009). Given the inverted U shaped association between catecholamine levels and executive cognition, the empirical literature is particularly clear on the need to take into account resting or pretask catecholamine levels when examining the relation of COMT genotype to measured executive cognitive ability (Dickinson & Elvevåg, 2009). Specifically, studies demonstrate that increased catecholamine availability, as with the presence of the Met allele in Val158Met, is associated with greater executive cognitive ability when resting catecholamine levels are low, but with reduced executive cognitive ability when pretask levels are high (Mattay et al., 2003; Qin et
Dev Psychobiol. Author manuscript; available in PMC 2017 January 18.
Blair et al.
Page 3
Author Manuscript
al., 2012) or when COMT activity is inhibited (Farrell, Tunbridge, Brauetigam, & Harrison, 2012).
Author Manuscript
Although it is well established that background catecholamine levels are relevant to the relation of genes such as COMT to executive cognition, it is notable that few if any studies have examined the relation between COMT and executive cognitive ability using a prospective longitudinal design that takes into account the quality of early life experience. Adverse early experience, such as that associated with early life stress has been shown in both human and animal models to increase catecholamine and glucocorticoid output (Evans, 2003; McEwen and Gianaros, 2011; Meaney, 2001) and to be associated with a pattern of gene expression associated with increased reactivity and decreased regulation of the stress response (Miller et al., 2009). It is therefore likely that early life experience will moderate any relation between variation in the COMT gene and executive function ability. Specifically, among individuals with stressful early life experience, higher catecholamine availability due to less efficient catabolism, as in individuals with a Met allele for COMT Val158Met, would be associated with lower rather than higher executive function ability. In contrast, in keeping with the Yerkes-Dodson inverted U-shape curve, among individuals with greater early life stress, reduced catecholamine availability (more efficient catabolism) associated with the Val-Val genotype would be associated with higher executive function abilities.
Author Manuscript Author Manuscript
Given a theoretical and empirical basis for expected interaction between monoamine gene variants and early experience in the prediction of developmental outcomes, questions about the age in childhood at which associations among gene variants, early experience, and cognitive outcomes might be observed are of interest. Examination of COMT enzyme activity in postmortem human brain indicated a twofold increase between the neonatal period and adulthood (Tunbridge et al., 2006) with levels in childhood at approximately 50% of their adult values. Notably, one prior lab-based study with a small sample of children from middle to upper income homes found, as expected, an association between Met genotype and executive functions in 8 to 14 year olds (Diamond, Briand, Fossella, & Gehlbach, 2004). A second, with a large sequential cohort sample in Sweden found that the Val–Val genotype was associated with working memory ability in young children (age 6 years) but that the Met-Met genotype was associated with better working memory in early adolescence (Dumontheil et al., 2011). No prior studies of which we are aware, however, have examined interaction between COMT and early experience in children with sample sizes large enough to produce reliable estimates of interaction effects. It is not known whether variation in early adversity in the typical range might interact with genetic background to influence trajectories of aspects of development such as executive function abilities in childhood. Here, we examine expected gene-environment interaction with a diverse prospective longitudinal sample of children and families in predominantly non-urban and low-income communities in two regions of high poverty in the US. It has been shown previously in this sample that early environmental adversity was prospectively associated with elevated cortisol levels in children through age 48 months (Blair et al., 2011a), and that elevated cortisol in the early toddler period partially mediated a relation between early adversity and
Dev Psychobiol. Author manuscript; available in PMC 2017 January 18.
Blair et al.
Page 4
Author Manuscript
lower performance on a battery of executive function tasks (Blair et al., 2011b). Here, we build on these prior findings to test the hypothesis that COMT Val158Met genotype will interact with cumulative risk in the family environment in the prediction of executive function development between ages 3 and 5 years. Specifically, the valine variant of COMT Val158Met will be associated with a higher level of executive in the context of high early adversity while the methionine variant will be associated with a higher level of executive function in the context of low early adversity.
METHODS Participants
Author Manuscript
The Family Life Project (FLP) was designed to study young children and their families in two of the four major geographical areas of the United States with high poverty rates. Specifically, three counties in eastern North Carolina and three counties in central Pennsylvania were selected to be indicative of the Black South and Appalachia, respectively. The FLP adopted a developmental epidemiological design in which sampling procedures were employed to recruit a representative sample of 1,292 children whose families resided in one of the six counties at the time of the child's birth. Low-income families in both states and African American families in NC were over-sampled. African American families were not over-sampled in PA because African Americans made up
